Process for synthesis of heteroaryl-substituted urea compounds useful as antiinflammatory agents

ABSTRACT

Disclosed are novel processes and novel intermediate compounds for preparing aryl-and heteroaryl-substituted urea compounds of the formula(I) wherein Ar 1 , Ar 2 , L, Q and X are described herein. The product compounds are useful in pharmaceutic compositions for treating diseases or pathological conditions involving inflammation such as chronic inflammatory diseases.

RELATED APPLICATION DATA

[0001] This application is a divisional application of U.S. applicationSer. No. 09/611,109.

TECHNICAL FIELD OF THE INVENTION

[0002] This invention relates to novel processes for preparing newaryl-and heteroaryl-substituted urea compounds of formula (I):

[0003] wherein Ar₁, Ar₂, X, L and Q are defined below, which are usefulfor treating diseases and pathological conditions involving inflammationsuch as chronic inflammatory disease.

BACKGROUND OF THE INVENTION

[0004] Aryl- and heteroaryl-substituted ureas have been described asinhibitors of cytokine production. Examples of such compounds arereported in WO 99/23091 and in WO 98/52558. These inhibitors aredescribed as effective therapeutics in cytokine-mediated diseases,including inflammatory and autoimmune diseases.

[0005] A key step in the synthesis of these compounds is the formationof the urea bond. Various methods have been reported to accomplish this.For example, as reported in the above references, an aromatic orheteroaromatic amine, II, may be reacted with an aromatic orheteroaromatic isocyanate III to generate the urea IV (Scheme I)

[0006] If not commercially available, one may prepare the isocyanate IIIby reaction of an aryl or heteroaryl amine Ar₂NH₂ with phosgene or aphosgene equivalent, such as bis(trichloromethyl) carbonate(triphosgene) (P. Majer and R. S. Randad, J. Org. Chem. 1994, 59, 1937)or trichloromethyl chloroformate (diphosgene). K. Kurita, T. Matsumuraand Y. Iwakura, J. Org. Chem. 1976, 41, 2070) to form the isocyanateIII, followed by reaction with Ar₁NH₂ to provide the urea. Otherapproaches to forming the urea known in the chemical literature are toform a carbamate, as shown in Scheme II below, by reaction of an aminewith a chloroformate derivative, such as phenyl chloroformate (B.Thavonekham, Synthesis, 1997, 1189), chloromethyl chloroformate (T.Patonay, E. Patonay-Peli, L Zolnai and F. Mogyorodi, SyntheticCommunications, 1996, 26, 4253), p-nitrophenyl chloroformate (J. Gante,Chem. Ber. 1965, 98, 3334), or 2,4,5-trichlorophenyl chloroformate (A.W. Lipkowski, S. W. Tam and P. S. Portoghese, J. Med. Chem. 1986, 29,1222) to form a carbamate V. This may then be reacted with an aryl orheteroaryl amine (II) to provide urea IV (Scheme II- reaction withphenyl chloroformate shown). The synthesis of ureas through(phenoxycarbonyl)tetrazole (R. W. Adamiak, J. Stawinski, TetrahedronLett. 1977, 1935) or 1,1′-carbonylbisbenzotriazole (A. R. Katritzky, D.P. M. Pleynet and B. Yang, J. Org. Chem. 1997, 62, 4155) has beenreported. In addition, preparation of ureas by catalytic carbonation ofamines with carbon monoxide or carbon dioxide has been documented in theliterature (N. Sonoda, T. Yasuhara, K. Kondo, T. Ikeda and S. Tsutsumi,J. Am. Chem. Soc. 1971, 93, 691; Y. Morimoto, Y. Fujiwara, H. Taniguchi,Y. Hori and Y.

[0007] Nagano, Tetrahedron Lett. 1986, 27, 1809). In each of thesecases, Ar₁ and Ar₂ may be modified before and/or after the ureaformation to produce desired compounds.

[0008] Each of the methods described above suffer from one or moredisadvantages. For example, phosgene and phosgene equivalents arehazardous and dangerous to use, particularly in large-scaleapplications. In addition the isocyanate intermediate III is not stableand may undergo decomposition during preparation and storage. The ureaformation may be done using a phenyl carbamate, as illustrated in SchemeII and U.S. application Ser. No. 09/484,638. However, the by-productphenol formed in the urea synthesis does not have sufficient watersolubility to be easily removed by water washing especially at largescale. Thus it may require multiple washing and several crystallizationsto obtain highly pure product. For these reasons these methods are notwell-suited for industrial-scale production.

[0009] U.S. application Ser. No. 09/484,638 also discloses the synthesisof substituted naphthyl amino intermediates for use in making aryl-andheteroaryl-substituted urea compounds of the formula(I) as describedtherein. This synthesis begins with 4-aminonapthol which is protectedwith a Boc (tert-butoxycarbonyl) group on the amine prior to alkylationand deprotection. This procedure is also not amenable toindustrial-scale production. The starting 4-aminonaphthol is veryexpensive and not available in large quantity. In addition theprotection and deprotection steps are tedious and add to the expense.

[0010] Disclosed herein are novel processes for making the aryl-andheteroaryl-substituted urea compounds of the formula(I) including thosedisclosed in U.S. application Ser. No. 09/484,638 and novelintermediates useful in such processes.

BRIEF SUMMARY OF THE INVENTION

[0011] It is therefore an object of this invention to provide a generaland cost-effective process for the preparation of the aryl- andheteroaryl-substituted urea compounds of the formula(I) shown below:

[0012] comprising the steps of:

[0013] reacting of intermediate of formula (II) with intermediate offormula (IV) to produce the product compound of formula (I):

[0014] wherein Ar₁, Ar₂, L, Q, X and Ra are as described below.

[0015] In addition, this invention provides efficient methods forpreparing intermediates used in the preparation of preferredcytokine-inhibiting aryl-and heteroaryl-substituted ureas. Theseprocesses are especially well-suited for preparation of these compoundson an industrial scale.

DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention is directed to the synthesis of compoundshaving formula (I):

[0017] wherein:

[0018] Ar₁ is a heterocyclic group selected from the group consisting ofphenyl, pyridine, pyridone, pyrrole, pyrrolidine, pyrazole, imidazole,oxazole, thiazole, furan and thiophene; wherein Ar₁ is optionallysubstituted by one or more R₁, R₂ or R₃;

[0019] Ar₂ is:

[0020]  phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl,tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran,indanyl, indenyl or indole each being optionally substituted with one tothree R₂ groups;

[0021] L, a linking group, is:

[0022] C₁₋₁₀ saturated or unsaturated branched or unbranched carbonchain;

[0023] wherein one or more methylene groups are optionally independentlyreplaced by O,N or S; and

[0024] wherein said linking group is optionally substituted with 0-2 oxogroups and one or more C₁₋₄ branched or unbranched alkyl optionallysubstituted by one or more halogen atoms;

[0025] or L is a cyclic group which is:

[0026] a) a C₅₋₈ cycloalkyl or cycloalkenyl optionally substituted with1-2 oxo groups, 1-3 C₁₋₄ branched or unbranched alkyl, C₁₋₄alkoxy orC₁₋₄alkylamino chains;

[0027] b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine,pyrimidine, pyridinone, dihydropyridinone, maleimide, dihydromaleimide,piperdine, piperazine or pyrazine each being optionally independentlysubstituted with 1-3 C₁₋₄ branched or unbranched alkyl, C₁₋₄alkoxy,hydroxy, cyano, mono- or di-(C₁₋₃alkyl)amino, C₁₋₆alkyl-S(O)_(q), orhalogen;

[0028] wherein said cyclic group is optionally attached to a C₁₋₄saturated or unsaturated branched or unbranched carbon chain whereinsaid carbon chain is in turn covalently attached to Q, said carbon chainis optionally partially or fully halogenated and wherein one or moremethylene groups are optionally replaced by O, NH, S(O), S(O)₂ or S,wherein said methylene groups are further optionally independentlysubstituted with 1-2 oxo groups and one or more C₁₋₄ branched orunbranched alkyl optionally substituted by one or more halogen atoms;

[0029] Q is selected from the group consisting of:

[0030] a) phenyl, naphthyl, pyridine, pyrimidine, pyridazine, imidazole,benzimidazole, furan, thiophene, pyran, naphthyridine,oxazo[4,5-b]pyridine and imidazo[4,5-b]pyridine, which are optionallysubstituted with one to three groups selected from the group consistingof halogen, C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, mono- ordi-(C₁₋₃alkyl)amino, C₁₋₆alkyl-S(O)_(m) and phenylamino wherein thephenyl ring is optionally substituted with one to two groups selectedfrom the group consisting of halogen, C₁₋₆alkyl and C₁₋₆alkoxy;

[0031] b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone,1,3-dioxanone, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholinesulfoxide, thiomorpholine sulfone, piperidine, piperidinone,tetrahydropyrimidone, cyclohexanone, cyclohexanol, pentamethylenesulfide, pentamethylene sulfoxide, pentamethylene sulfone,tetramethylene sulfide, tetramethylene sulfoxide and tetramethylenesulfone which are optionally substituted with one to three groupsselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy,mono- or di-(C₁₋₃alkyl)amino-C₁₋₃alkyl, phenylamino-C₁₋₃alkyl andC₁₋₃alkoxy-C₁₋₃alkyl;

[0032] c) C₁₋₆alkoxy, secondary or tertiary amine wherein the aminonitrogen is covalently bonded to groups selected from the groupconsisting of C₁₋₃alkyl and C₁₋₅alkoxyalkyl and phenyl wherein thephenyl ring is optionally substituted with one to two groups selectedfrom the group consisting of halogen, C₁₋₆alkoxy, hydroxy or mono- ordi-(C₁₋₃alkyl)amino, C₁₋₆alkyl-S(O)_(r) and phenyl-S(O)_(r), wherein thephenyl ring is optionally substituted with one to two groups consistingof halogen, C₁₋₆alkoxy, hydroxy and mono- or di-(C₁₋₃alkyl)amino;

[0033] R₁ is selected from the group consisting of:

[0034] (a) C₃₋₁₀ branched or unbranched alkyl, which may optionally bepartially or fully halogenated, and optionally substituted with one tothree phenyl, naphthyl or heterocyclic groups selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; eachsuch phenyl, naphthyl or heterocycle selected from the group hereinabovedescribed, being substituted with 0 to 5 groups selected from the groupconsisting of halogen, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, C₃₋₈ cycloalkyl, C₅₋₈cycloalkenyl, hydroxy, cyano, C₁₋₃alkyloxy which is optionally partiallyor fully halogenated, NH₂C(O) and di(C₁₋₃)alkylaminocarbonyl;

[0035] (b) C₃₋₇ cycloalkyl selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, which areoptionally partially or fully halogenated and optionally substitutedwith one to three C₁₋₃alkyl groups, or an analog of such cycloalkylgroup wherein one to three ring methylene groups are replaced by groupsindependently selected from O, S, CHOH, >C═O, >C═S and NH;

[0036] (c) C₃₋₁₀ branched alkenyl optionally partially or fullyhalogenated, and optionally substituted with one to three C₁₋₅ branchedor unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with eachsuch heterocyclic group being independently selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, andeach such phenyl, naphthyl or heterocyclic group being substituted with0 to 5 groups selected from halogen, C₁₋₆ branched or unbranched alkylwhich is optionally partially or fully halogenated, cyclopropyl,cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl, bicycloheptanyl, hydroxy, cyano, C₁₋₃alkyloxy which isoptionally partially or fully halogenated, NH₂C(O) and mono- ordi(C₁₋₃)alkylaminocarbonyl;

[0037] (d) C₅₋₇ cycloalkenyl selected from the group consisting ofcyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein suchcycloalkenyl group is optionally substituted with one to three C₁₋₃alkylgroups;

[0038] (e) cyano; and,

[0039] (f) methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;

[0040] R₂ is selected from the group consisting of:

[0041] a C₁₋₆ branched or unbranched alkyl optionally partially or fullyhalogenated, acetyl, aroyl, C₁₋₄ branched or unbranched alkoxyoptionally partially or fully halogenated, halogen, methoxycarbonyl andphenylsulfonyl;

[0042] R₃ is selected from the group consisting of:

[0043] a) a phenyl, naphthyl or heterocyclic group selected from thegroup consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl,isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl,naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolylwherein such phenyl, naphthyl or heterocyclic group is optionallysubstituted with one to five groups selected from the group consistingof a C₁₋₆ branched or unbranched alkyl, phenyl, naphthyl, heterocycleselected from the group hereinabove described, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C₁₋₅alkyl,naphthyl C₁₋₅alkyl, halo, hydroxy, cyano, C₁₋₃alkyloxy which mayoptionally be partially or fully halogenated, phenyloxy, naphthyloxy,heteraryloxy wherein the heterocyclic moiety is selected from the grouphereinabove described, nitro, amino, mono- or di-(C₁₋₃)alkylamino,phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclylmoiety is selected from the group hereinabove described, NH₂C(O), amono- or di-(C₁₋₃)alkyl aminocarbonyl, C₁₋₅alkyl-C(O)—C₁₋₄alkyl,amino-C₁₋₅alkyl, mono- or di-(C₁₋₃) alkylamino-C₁₋₅alkyl, amino-S(O)₂,di-(C₁₋₃)alkylamino-S(O)₂, R₄—C₁₋₅alkyl, R₅—C₁₋₅ alkoxy,R₆—C(O)—C₁₋₅alkyl and R₇—C₁₋₅alkyl-N(R₈)—;

[0044] b) a fused aryl selected from the group consisting ofbenzocyclobutanyl, indanyl, indenyl, dihydronaphthyl,tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or afused heterocyclyl selected from cyclopentenopyridine,cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine,cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine,cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline,cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole,cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole,cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene;wherein the fused aryl or fused heterocyclyl ring is substituted with 0to 3 groups independently selected from phenyl, naphthyl, heterocyclylselected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl, and isothiazolyl, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, halo, cyano, C₁₋₃alkyloxywhich is optionally partially or fully halogenated, phenyloxy,naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selectedfrom the group hereinabove described, nitro, amino, mono- ordi-(C₁₋₃)alkylamino, phenylamino, naphthylamino, heterocyclylaminowherein the heterocyclyl moiety is selected from the group hereinabovedescribed, NH₂C(O), a mono- or di-(C₁₋₃)alkyl aminocarbonyl,C₁₋₄alkyl-OC(O), C₁₋₅alkyl-C(O)—C₁₋₄ branched or unbranched alkyl, anamino-C₁₋5 alkyl, mono- or di-(C₁₋₃)alkylamino-C₁₋₅alkyl, R₉—C₁₋₅alkyl,R₁₀—C₁₋₅alkoxy, R₁₁—C (O)—C₁₋₅alkyl and R₁₂—C₁₋₅alkyl-N(R₁₃)—;

[0045] c) cycloalkyl selected from the group consisting ofcyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl and bicycloheptanyl, wherein the cycloalkyl is optionallypartially or fully halogenated and optionally substituted with one tothree C₁₋₃alkyl groups;

[0046] d) C₅₋₇ cycloalkenyl, selected from the group consisting ofcyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein suchcycloalkenyl group is optionally substituted with one to three C₁₋₃alkylgroups;

[0047] e) acetyl, aroyl, alkoxycarbonylalkyl and phenylsulfonyl; and

[0048] f) C₁₋₆ branched or unbranched alkyl optionally partially orfully halogenated;

[0049] R₁ and R₂ taken together optionally form a fused phenyl orpyridinyl ring;

[0050] each R₈ or R₁₃ is independently selected from the groupconsisting of:

[0051] hydrogen and C₁₋₄ branched or unbranched alkyl optionallypartially or fully halogenated;

[0052] each R₄, R₅, R₆, R₇, R₉, R₁₀, R₁₁ and R₁₂ is independentlyselected from the group consisting of:

[0053] morpholine, piperidine, piperazine, imidazole and tetrazole;

[0054] m is 0, 1 or 2;

[0055] q is 0, 1 or 2;

[0056] r is 0, 1 or 2;

[0057] t is 0, 1 or 2; and

[0058] X is O or S.

[0059] The compounds of the invention may be prepared as physiologicallyand pharmaceutically acceptable salts, as may seem appropriate to one ofordinary skill in the art.

[0060] The compounds produced by the novel process of the invention areonly those which are contemplated to be ‘chemically stable’ as will beappreciated by those skilled in the art. For example, a compound whichwould have a ‘dangling valency’, or a ‘carbanion’ are not compoundscontemplated to be made by the novel process.

[0061] All terms as used herein in this specification, unless otherwisestated, shall be understood in their ordinary meaning as known in theart. For example, “C₁₋₄alkoxy” is a C₁₋₄alkyl with a terminal oxygen,such as methoxy, ethoxy, propoxy, pentoxy and hexoxy. All alkyl, alkenyland alkynyl groups shall be understood as being branched or unbranchedwhere structurally possible and unless otherwise specified. Other morespecific definitions are as follows:

[0062] The term “aroyl” as used in the present specification shall beunderstood to mean “benzoyl” or “naphthoyl”.

[0063] NMP: 1-methyl-2-pyrrolidinone;

[0064] THF: tetrahydrofuran;

[0065] DMF: N,N′-dimethylformamide;

[0066] DMAC: N-N′-dimethylacetamide;

[0067] DMSO: dimethylsulfoxide;

[0068] DMAP: 4-dimethylaminopyridine;

[0069] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene;

Process for Making Compounds of the Formula (I)

[0070] The Novel Process Comprises:

[0071] STEP 1:

[0072] Reacting in a suitable solvent an amino-heterocycle NH₂—Ar₁ witha haloformate RaOC(X)Ha, wherein Ra represents C₂₋₃ halocarbon,preferably 2,2,2-trichloroethyl, and Ha represents halogen, preferablychloro, X is as defined above, in the presence of a suitable base, toproduce carbamate of the formula (II):

[0073] Preferable formate RaOC(X)Ha are those, which upon hydrolysis ofthe formula(II) intermediates, will form a water soluble byproduct whichis easily removed by aqueous washing, such byproduct would be, forexample, 2,2,2-trichloroethanol. Examples of preferred RaOCOHa aretrichloroethyl chloroformate or trichloroethyl chlorothioformate.Accordingly, a preferred compound of the formula(II) is:

[0074] Synthesis of amino-heterocycle NH₂—Ar₁ has been illustrated inU.S. patent application Ser. No. 09/484,638, incorporated herein byreference. A particularly preferred compound of the formula(II) is whereAr₁ is 1-tolyl-3-t-butyl-pyrazole-5-yl.

[0075] Reaction conditions such as the selection of a suitable solventand temperature is within the skill of the ordinary artisan depending onthe particular compounds desired. Typically, the reaction of step 1 isin a non-aqueous or an aqueous solvent, preferably THF or ethyl acetate,in the presence of a suitable base such as tertiary amine for exampletriethylamine, diisopropylethylamine, N-methylpyrrolidine,DBU(1,8-diazabicyclo[5.4.0]undec-7-ene), DMAP(4-dimethylaminopyridine),N-methylmorpholine, pyridine, methyl pyridine or inorganic bases such assodium hydroxide, sodium carbonate, sodium bicarbonate, potassiumhydroxide, potassium carbonate and potassium bicarbonate. Preferredsuitable bases for step 1 are diisopropylethylamine, NaOH orN-methylpyrrolidine. The reaction occurs at a temperature of about0-100° C., preferably 5-15° C., for about 0.5-24 hrs, preferably 3-4hrs.

[0076] STEP 2

[0077] For certain preferred embodiments, Step 2 proceeds as follows.Reacting a Z—Ar₂—MH, where Z is a nitro or nitroso group, M is O, S, orNH, and Ar₂ is as defined hereinabove, with a Y—J—Q moiety in a suitablesolvent to produce the intermediate of formula (III)

[0078] wherein L and Q are as defined hereinabove , Y is a leaving groupsuch as a halogen and M—J constitutes L;

[0079] A suitable solvent for the above reaction would be a polarnon-protic organic solvent, such as acetonitrile, DMF(N,N′-dimethylformamide), DMAC (N-N′-dimethylacetamide), DMSO(dimethylsulfoxide) and NMP (1-methyl-2-pyrrolidinone), preferably NMP,at a temperature of about 50-100° C., preferably between 75-95° C., forabout 0.5-24 hrs, preferably 3-4 hrs.

[0080] For other embodiments of L, analogous methods can be found inU.S. patent application Ser. Nos. 09/484,638 and 09/505,582 incorporatedin their entirety by reference.

[0081] STEP 3

[0082] Reducing compound of formula (III) with catalytic hydrogenationor non-catalytic reduction to produce the intermediate of formula (IV):

[0083] Catalytic hydrogenation is preferred, a preferred catalyst isPd/C. Reaction conditions such as the selection of a suitable solventand temperature is within the skill of the ordinary artisan. Thecatalytic hydrogenation with respect to H₂ pressure and time can bevaried, a preferable hydrogenation occurs under about 30 psi for about 1hr-24 hours.

[0084] STEP 4

[0085] Reacting the intermediate of formula (II) with the intermediateof formula (IV) with or without base, preferably with a base. A suitablebase will be one such as tertiary amine for example triethylamine,diisopropylethylamine, N-methylpyrrolidine, DBU, DMAP,N-methylmorpholine, pyridine, methyl pyridine or an inorganic base suchas sodium hydroxide, sodium carbonate, sodium bicarbonate, potassiumhydroxide, potassium carbonate and potassium bicarbonate. Preferredbases are diisopropylethylamine or N-methylpyrrolidine. The reactiontakes place in the presence of suitable solvent to produce the productof formula (I):

[0086] Reaction conditions such as the selection of a suitable solvent,base and temperature can be varied according to the specific compound ofthe formula(I) that is desired. The reaction can be run in a suitablepolar, or a suitable non-polar solvent such as methylene chloride orchloroform or in heptane, hexane, cyclohexane, ethyl acetate, benzene,toluene, xylene, tetrahydropfuran, dioxane, ethyl ether, methyl butylether or in a biphasic aqueous/organic mixture. Preferably the solventwill be a polar non-protic organic solvent such asNMP(1-methyl-2-pyrrolidinone), acetonitrile, DMF(N,N-dimethylformamide),DMAC(N,N-dimethylacetamide) or DMSO, more preferably DMSO or NMP, whichis heated to an appropriate temperature, preferably about 55-60° C. forabout 1.5 hours. Particular separation methods depending on the compounddesired will be apparent to those of ordinary skill in the art. Apreferred method is shown in Example 1 in the present specification.

[0087] A preferred subgeneric aspect of the invention comprises aprocess of producing compounds of the formula(I) wherein Ar₂ isnaphthyl, tetrahydronaphthyl, indanyl or indenyl.

[0088] A more preferred subgeneric aspect of the invention comprises aprocess of producing compounds of the formula(I) wherein Ar₂ isnaphthyl.

[0089] A yet more preferred subgeneric aspect of the invention comprisesa process of producing compounds of the formula (I), as described in theimmediate previous paragraph, wherein:

[0090] Ar₁ is thiophene or pyrazole;

[0091] Ar₂ is 1-naphthyl;

[0092] L is C₁₋₆ saturated or unsaturated branched or unbranched carbonchain wherein

[0093] one or more methylene groups are optionally independentlyreplaced by O, N or S; and wherein said linking group is optionallysubstituted with 0-2 oxo groups and one or more C₁₋₄ branched orunbranched alkyl optionally substituted by one or more halogen atoms;

[0094] or L is cyclopentenyl, cyclohexenyl, cycloheptenyl, eachoptionally substituted with an oxo group or 1-3 C₁₋₄ branched orunbranched alkyl, C₁₋₄alkoxy or C₁₋₄alkylamino; or L is phenyl,pyridine, furan or thiophene each being optionally independentlysubstituted with 1-3 C₁₋₄ branched or unbranched alkyl, C₁₋₄alkoxy,hydroxy, cyano, mono- or di-(C₁₋₃alkyl)amino, C₁₋₆alkyl-S(O)_(q) orhalogen;

[0095] wherein said cyclic group is optionally attached to a C₁₋₄saturated or unsaturated branched or unbranched carbon chain whereinsaid carbon chain is in turn covalently attached to Q, said carbon chainis optionally partially or fully halogenated and wherein one or moremethylene groups are optionally replaced by O, NH, S(O), S(O)₂ or S,wherein said methylene groups are further optionally independentlysubstituted with 1-2 oxo groups and one or more C₁₋₄ branched orunbranched alkyl optionally substituted by one or more halogen atoms;

[0096] R₁ is C₃₋₄alkyl branched or unbranched, cyclopropyl orcyclohexanyl optionally partially or fully halogenated and optionallysubstituted with one to three C₁₋₃alkyl groups;

[0097] R₃ is selected from the group consisting of C₁₋₄alkyl branched orunbranched optionally partially or fully halogenated, cyclopentanyloptionally partially or fully halogenated and optionally substitutedwith one to three C₁₋₃alkyl groups,

[0098] phenyl, pyridinyl each being optionally substituted with one tofive groups selected from the group consisting of a C₁₋₆ branched orunbranched alkyl, phenyl, naphthyl, pyridinyl, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C₁₋₅alkyl,naphthyl C₁₋₅alkyl, halo, hydroxy, cyano, C₁₋₃alkyloxy which mayoptionally be partially or fully halogenated, phenyloxy, naphthyloxy,pyridinyloxy, nitro, amino, mono- or di-(C₁₋₃)alkylamino, phenylamino,naphthylamino, pyridinylamino, NH₂C(O), a mono- or di-(C₁₋₃)alkylaminocarbonyl, C₁₋₅alkyl-C(O)—C₁₋₄alkyl, amino-C₁₋₅alkyl, mono- ordi-(C₁₋₃)alkylamino-C₁₋₅alkyl, amino-S(O)₂, di-(C₁₋₃)alkylamino-S(O)₂,R₄—C₁₋₅alkyl, R₅-alkoxy, R6—C(O)—C₁₋₅alkyl and R₇—C₁₋₅alkyl—N(R₈)—; andR₃ is alkoxycarbonylalkyl;

[0099] A yet further preferred subgeneric aspect of the inventioncomprises a process of producing compounds of the formula (I), asdescribed in the immediate previous paragraph, wherein Ar₁ is pyrazole.

[0100] A still yet further preferred subgeneric aspect of the inventioncomprises a process of producing compounds of the formula (I), asdescribed in the immediate previous paragraph, wherein L is C₁₋₅saturated carbon chain wherein one or more methylene groups areoptionally independently replaced by O, N or S; and wherein said linkinggroup is optionally substituted with 0-2 oxo groups and one or more C₁₋₄branched or unbranched alkyl optionally substituted by one or morehalogen atoms;

[0101] More particularly preferred embodiments of the process of theinvention is where L is propoxy, ethoxy, methoxy, methyl, propyl, C₃₋₅acetylene or methylamino each being optionally substituted as describedherein and Q is morpholine.

[0102] A even more particularly preferred embodiment of L is ethoxyoptionally substituted, the base is diisopropylethylamine and the polarnon-protic organic solvent is DMSO.

[0103] In order that this invention be more fully understood, thefollowing examples are set forth. These examples are for the purpose ofillustrating preferred embodiments of this invention, and are not to beconstrued as limiting the scope of the invention in any way.

SYNTHETIC EXAMPLES Example 11-[3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea

[0104]

[0105] 5-Amino-3-t-butyl-1-p-tolylpyrazole Hydrochloride:

[0106] A solution of pivaloylacetonitrile (750 g, 6.0 mol) andp-tolylhydrazine hydrochloride (660 g, 4.2 mol) in methanol (2.8 L) wasrefluxed for 3 h. Heptane was added, and methanol was removed bydistillation. The product was crystallized from the solution, collectedby filtration and dried in vacuum oven to constant weight. Yield: 1.05kg, 94%. ¹H NMR δ (CDCl₃) 7.50 (d, 2H), 7.30 (d, 2H), 5.60 (s, 1H), 2.45(s, 3H), 1.40 (s, 9H). MS (CI) m/z 229 (M⁺+H).

[0107]5-(2,2,2-Trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole:

[0108] A mixture of 5-amino-3-t-butyl-1-p-tolylpyrazole hydrochloride(300 g, 1.13 mol), water (0.9 L), EtOAc (2.1 L) and NaOH (117 g, 2.84mol) was stirred between 5-15° C. for 30 min. To this mixture,2,2,2-trichloroethyl chloroformate (342 g, 1.58 mol) was added over 1 hbetween 5-15° C. The mixture was stirred at room temperature for 2 h,and then the aqueous layer was separated from the EtOAc layer. The EtOAclayer was washed with brine (2×0.9 L) and dried over MgSO₄ (60 g). TheEtOAc layer was collected by filtration. To this solution, heptane wasadded. A part of the solution was removed by distillation. The productwas crystallized from the solution, collected by filtration and dried invacuum oven to constant weight. Yield: 409 g, 90%. ¹H NMR (CDCl₃) δ 7.40(d, 2H), 7.30 (d, 2H), 6.40 (s, 1H), 4.80 (s, 2H), 2.40 (s, 3H), 1.40(s, 9H). MS (EI) m/z 404 (M⁺).

[0109] 4-Nitro-1-(2-morpholinethoxy)naphthalene:

[0110] A mixture of 4-nitro-1-hydroxynaphthalene (194 g, 1.0 mol),4-(2-chloroethyl)morpholine hydrochloride (264 g, 1.4 mol), NaOH (58 g,1.4 mol), K₂CO₃ (339 g, 2.4 mol) and 1-methyl-2-pyrrolidinone (1.0 L)was heated to 90-100° C. and held for 1-2 h. The mixture was cooled to40° C. and water was slowly added. The mixture was cooled to 5° C. andheld for 4 h. The product was collected by filtration, washed withwater, cyclohexane and dried in vacuum to constant weight. Yield: 227 g,75%. ¹H NMR (CDCl₃) δ 8.76 (d, 1H), 8.38 (m, 2H), 7.74 (dd, 1H), 7.58(dd, 1H), 6.79 (d, 1 H), 4.38 (dd, 2H), 3.74 (d, 4H), 2.98 (dd, 2H),2.65 (d, 4H). MS (EI) m/z 303 (M +1).

[0111] 4-Amino-1-(2-Morpholinethoxy)naphthalene Hydrochloride:

[0112] A mixture of 4-nitro-1-(2-morpholinethoxy)naphthalene (40 g, 0.13mol), MeOH (280 mL) and Pd/C (50% water, 1.2 g) was hydrogenated under30 psi for 24 h. The catalyst was filtered through a layer ofdiatomaceous earth under nitrogen. To this filtrate 20 mL of HCl (37%)and cyclohexane (200 mL) were added. The solvent was removed underreduced pressure and the product collected by filtration. The productwas dried in vacuum to constant weight. Yield: 33 g, 82%. ¹H NMR (DMSO)δ 8.38 (d, 1H), 8.00 (d, 1H), 7.72 (dd, 1H), 7.64 (m, 2H), 7.05 (d, 1H),4.62 (s, 2H), 4.00 (b, 4H), 3.88 (s, 2H), 3.40 (b m/z 273 (M⁺).

[0113]1-[3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea:

[0114] A solution of5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (10.6g, 26 mmol), 4-amino-1-(2-morpholinethoxy)naphthalene (free base fromHCl salt above, 7.16 g, 26 mmol), diisopropylethylamine (3.2 g, 25 mmol)and DMSO (75 mL) was heated to 55-60° C. and held for 1.5 h. To thissolution, ethyl acetate (100 mL) was added. The organic layer was washedwith brine (4×50 mL), and dried over MgSO₄. The solvent was removedunder reduced pressure, and residue was crystallized from acetonitrile(50 mL) at 0° C. The product was collected by filtration, recrystallizedfrom isopropanol and dried in vacuum to constant weight, m.p.: 151-152°C. Yield: 11.4g, 87%. ¹H NMR (DMSO) δ 8.75 (s, 1H), 8.51 (s, 1H), 8.21(d, 1H), 7.85 (d, 1H), 7.65 (d, 1H), 7.55 (m, 2H), 7.49 (dd, 1H), 7.35(dd, 1H), 6.95 (d, 1H, 6.38 (s, 1H), 4.26 (dd, 2H), 3.60 (dd, 4H), 2.81(dd, 2H), 2.55 (dd, 4H), 2.38 (s, 3H), 1.29 (s, 9H). MS (CI) m/z 528(M⁺+1).

[0115] The following additional non-limiting examples can be made usingthe novel process of the invention:

Example 2[-3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl]-3-{4-[5-(morpholin4-ylmethyl)fur-2-yl]naphthalen-1-yl}urea

[0116]

[0117] A solution of5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26mmol), 1 -amino-4-[5-(morpholin-4-ylmethyl)fur-2-yl]naphthalene (26mmol), diisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL)is added. The organic layer is washed with brine (4×50 mL), and driedover MgSO₄. The solvent is removed under reduced pressure, and residueis crystallized from a suitable solvent such as acetonitrile (50 mL) at0° C. The product is collected by filtration and recrystallized from asuitable solvent such as isopropanol and dried in vacuum to constantweight.

Example 31-[3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl]-3-{4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl}urea

[0118]

[0119] A solution of5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26mmol), 1-amino-4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalene (26mmol), duisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL)is added. The organic layer is washed with brine (4×50 mL), and driedover MgSO₄. The solvent is removed under reduced pressure, and residueis crystallized from a suitable solvent such as acetonitrile (50 mL) at0° C. The product is collected by filtration and recrystallized from asuitable solvent such as isopropanol and dried in vacuum to constantweight.

Example 41-[3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl]-3-(4-{6-[(3-methoxypropyl)methylamino]pyridin-3-yl}naphthalen-1-yl)urea

[0120]

[0121] A solution of5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26mmol), 1-amino-4-{6-[(3-methoxypropyl)methylamino]pyridin-3-yl}naphthalene (26mmol), diisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL)is added. The organic layer is washed with brine (4×50 mL), and driedover MgSO₄. The solvent is removed under reduced pressure, and residueis crystallized from a suitable solvent such as acetonitrile (50 mL) at0° C. The product is collected by filtration and recrystallized from asuitable solvent such as isopropanol and dried in vacuum to constantweight.

Example 51-[3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl]-3-[4-(3-pyridin-4-yl-propox)naphthalen-1-yl]-urea

[0122]

[0123] A solution of5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26mmol), 1 -amino-4-(3-pyridin-4-ylpropoxy)naphthalene (26 mmol),diisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to 55-90° C.and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added.The organic layer is washed with brine (4×50 mL), and dried over MgSO₄.The solvent is removed under reduced pressure, and residue iscrystallized from a suitable solvent such as acetonitrile (50 mL) at 0°C. The product is collected by filtration and recrystallized from asuitable solvent such as isopropanol and dried in vacuum to constantweight.

Example 61-[3-tert-Butyl-1-(2-methylpyridin-5-yl)-1H-pyrazol-5-yl]-3-[4-(pyridin-4-yl-methoxy)naphthalen-1-yl]-urea

[0124]

[0125] A solution of5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-(2-methylpyridin-5-yl)pyrazole(26 mmol), 1-amino-4-(pyridin-4-ylmethoxy)naphthalene (26 mmol),diisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to 55-90° C.and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added.The organic layer is washed with brine (4×50 mL), and dried over MgSO₄.The solvent is removed under reduced pressure, and residue iscrystallized from a suitable solvent such as acetonitrile (50 mL) at 0°C. The product is collected by filtration and recrystallized from asuitable solvent such as isopropanol and dried in vacuum to constantweight.

Example 71-[3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl]-3-[4-(2-pyridin-4-yl-ethenyl)naphthalen-1-yl]-urea

[0126]

[0127] A solution of5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26mmol), 1-amino-4-(2-pyridin-4-yl-ethenyl)naphthalene (26 mmol),diisopropylethylamine (3.2 g, 25 mmol) and DMSO (75 mL) is heated to55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL)is added. The organic layer is washed with brine (4×50 mL), and driedover MgSO₄. The solvent is removed under reduced pressure, and residueis crystallized from a suitable solvent such as acetonitrile (50 mL) at0° C. The product is collected by filtration and recrystallized from asuitable solvent such as isopropanol and dried in vacuum to constantweight.

Example 81-(5-tert-Butyl-2-methyphenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]urea

[0128]

[0129] A solution of5-t-butyl-2-methyl-1-(2,2,2-trichloroethoxycarbonyl)aminobenzene (26mmol), 1-amino-4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalene (26mmol), diisopropylethylamine (3.2 g, 25 mmol) and DMSO (75 mL) is heatedto 55-60° C. and held for 1.5 h. To this solution, ethyl acetate (100mL) is added. The organic layer is washed with brine (4×50 mL), anddried over MgSO₄. The solvent is removed under reduced pressure, andresidue is crystallized from a suitable solvent such as acetonitrile (50mL) at 0° C. The product is collected by filtration and recrystallizedfrom a suitable solvent such as isopropanol and dried in vacuum toconstant weight.

What is claimed is:
 1. A compound of formula:

Ra represents C₂₋₃ halocarbon; Ar₁ is a heterocyclic group selected fromthe group consisting of phenyl, pyridine, pyridone, pyrrole,pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan andthiophene; wherein Ar₁ is optionally substituted by one or more R₁, R₂or R₃; R₁ is selected from the group consisting of: a) C₃₋₁₀ branched orunbranched alkyl, which may optionally be partially or fullyhalogenated, and optionally substituted with one to three phenyl,naphthyl or heterocyclic groups selected from the group consisting ofpyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each suchphenyl, naphthyl or heterocycle selected from the group hereinabovedescribed, being substituted with 0 to 5 groups selected from the groupconsisting of halogen, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, C₃₋₈ cycloalkyl, C₅₋₈cycloalkenyl, hydroxy, cyano, C₁₋₃alkyloxy which is optionally partiallyor fully halogenated, NH₂C(O) and di(C₁₋₃)alkylaminocarbonyl; b) C₃₋₇cycloalkyl selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl and bicycloheptanyl, which are optionally partially orfully halogenated and optionally substituted with one to three C₁₋₃alkylgroups, or an analog of such cycloalkyl group wherein one to three ringmethylene groups are replaced by groups independently selected from O,S, CHOH, >C═O, >C═S and NH; C₃₋₁₀ branched alkenyl optionally partiallyor fully halogenated, and optionally substituted with one to three C₁₋₅branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups,with each such heterocyclic group being independently selected from thegroup consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl andisothiazolyl, and each such phenyl, naphthyl or heterocyclic group beingsubstituted with 0 to 5 groups selected from halogen, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, cyano,C₁₋₃alkyloxy which is optionally partially or fully halogenated, NH₂C(O)and mono- or di(C₁₋₃)alkylaminocarbonyl; c) C₅₋₇ cycloalkenyl selectedfrom the group consisting of cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl andbicycloheptenyl, wherein such cycloalkenyl group is optionallysubstituted with one to three C₁₋₃alkyl groups; d) cyano; and, g)methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; R₂ is selected fromthe group consisting of: a C₁₋₆ branched or unbranched alkyl optionallypartially or fully halogenated, acetyl, aroyl, C₁₋₄ branched orunbranched alkoxy optionally partially or fully halogenated, halogen,methoxycarbonyl and phenylsulfonyl; R₃ is selected from the groupconsisting of: a) phenyl, naphthyl or heterocyclic group selected fromthe group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl,isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl,naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolylwherein such phenyl, naphthyl or heterocyclic group is optionallysubstituted with one to five groups selected from the group consistingof a C₁₋₆ branched or unbranched alkyl, phenyl, naphthyl, heterocycleselected from the group hereinabove described, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C₁₋₅alkyl,naphthyl C₁₋₅alkyl, halo, hydroxy, cyano, C₁₋₃alkyloxy which mayoptionally be partially or fully halogenated, phenyloxy, naphthyloxy,heteraryloxy wherein the heterocyclic moiety is selected from the grouphereinabove described, nitro, amino, mono- or di-(C₁₋₃)alkylamino,phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclylmoiety is selected from the group hereinabove described, NH₂C(O), amono- or di-(C₁₋₃)alkyl aminocarbonyl, C₁₋₅alkyl-C(O)—C₁₋₄alkyl,amino-C₁₋₅alkyl, mono- or di-(C₁₋₃)alkylamino-C₁₋₅alkyl, amino-S(O)₂,di-(C₁₋₃)alkylamino-S(O)₂, R₄-C₁₋₅alkyl, R₅—C₁₋₅alkoxy,R₆—C(O)—C₁₋₅alkyl and R₇—C₁₋₅alkyl-N(R₈)—; b) fused aryl selected fromthe group consisting of benzocyclobutanyl, indanyl, indenyl,dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl andbenzocycloheptenyl, or a fused heterocyclyl selected fromcyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine,cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine,cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline,cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline,cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole,cyclohexanobenzimidazole, cyclopentanobenzoxazole,cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole,cyclopentanothiophene and cyclohexanothiophene; wherein the fused arylor fused heterocyclyl ring is substituted with 0 to 3 groupsindependently selected from phenyl, naphthyl, heterocyclyl selected fromthe group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, andisothiazolyl, C₁₋₆ branched or unbranched alkyl which is optionallypartially or fully halogenated, halo, cyano, C₁₋₃alkyloxy which isoptionally partially or fully halogenated, phenyloxy, naphthyloxy,heterocyclyloxy wherein the heterocyclyl moiety is selected from thegroup hereinabove described, nitro, amino, mono- or di-(C₁₋₃)alkylamino,phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclylmoiety is selected from the group hereinabove described, NH₂C(O), amono- or di-(C₁₋₃)alkyl aminocarbonyl, C₁₋₄alkyl-OC(O),C₁₋₅alkyl-C(O)—C₁₋₄ branched or unbranched alkyl, an amino-C₁₋₅alkyl,mono- or di-(C₁₋₃)alkylamino-C₁₋₅alkyl, R₉—C₁₋₅alkyl, R₁₀—C₁₋₅alkoxy,R₁₁—C(O)—C₁₋₅alkyl and R₁₂—C₁₋₅alkyl-N(R₁₃)—; c) cycloalkyl selectedfrom the group consisting of cyclopentanyl, cyclohexanyl, cycloheptanyl,bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, wherein thecycloalkyl is optionally partially or fully halogenated and optionallysubstituted with one to three C₁₋₃alkyl groups; d) C₅₋₇ cycloalkenyl,selected from the group consisting of cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl andbicycloheptenyl, wherein such cycloalkenyl group is optionallysubstituted with one to three C₁₋₃alkyl groups; e) acetyl, aroyl,alkoxycarbonylalkyl and phenylsulfonyl; and f) C₁₋₆ branched orunbranched alkyl optionally partially or fully halogenated; R₁ and R₂taken together optionally form a fused phenyl or pyridinyl ring; each R₈or R₁₃ is independently selected from the group consisting of: hydrogenand C₁₋₄ branched or unbranched alkyl optionally partially or fullyhalogenated; each R₄, R₅, R₆, R₇, R₉, R₁₀, R₁₁ and R₁₂ is independentlyselected from the group consisting of: morpholine, piperidine,piperazine, imidazole and tetrazole; m is 0, 1or 2; q is 0, 1 or 2; r is0, 1 or 2; t is 0, 1 or 2; and X is O or S.
 2. The compound according toclaim 1, wherein the compound is the formula:

wherein Ar₁ is thiophene or pyrazole optionally substituted by one ormore R₁, R₂ or R₃; and X is O.
 3. A compound chosen from:


4. The compound according to claim 3 wherein the compound is:


5. A process of producing a compound of the formula(II) according toclaim 1

comprising: reacting an aminoheterocycle NH₂-Ar₁ with a formateRaOC(X)Ha, in a suitable solvent in the presence of a suitable base atabout 0 to 100° C. for about 0.5 to 24 hours, wherein Ra represents C₂₋₃halocarbon, and Ha represents halogen, X and Ar₁ are as defined in claim1, to produce a compound of the formula (II).
 6. The process accordingto claim 5 wherein Ra is 2,2,2-trichloroethyl, Ha is chloro, X is O, thesolvent is THF or ethyl acetate, the base is selected from the groupconsisting diisopropylethylamine, N-methylpyrrolidine and NaOH; thetemperature is about 5 to 15° C.; and the time is about 3 hours.
 7. Theprocess according to claim 6 wherein Ar₁ is thiophene or pyrazoleoptionally substituted by one or more R₁, R₂ or R₃.
 8. The processaccording to claim 5 wherein the product formula (II) is chosen from:


9. The process according to claim 8 wherein the product formula (II) is